Basics
Description
- Muscular dystrophies (MDs) are a heterogeneous group of disorders characterized by a slow degeneration of muscle with consequent weakness and contracture deformity. Cardiac muscle can be involved in some forms.
- MDs with childhood onset can be divided into 5 groups:
- Dystrophinopathies (i.e., Duchenne MD [DMD], Becker MD [BMD])
- Limb girdle MDs (LGMDs)
- Congenital MD (CMD)
- Facioscapulohumeral MD (FSH-MD)
- Emery-Dreifuss MD (EDMD)
- Types of MDs can be differentiated by their clinical features (i.e., pattern of muscle weakness, joint contractures), age of onset, genetic test results, and/or muscle biopsy.
Epidemiology
- Dystrophinopathies
- DMD: 1 per 3,500 boys (most common)
- BMD: 1 per 30,000 boys
- LGMD (childhood onset): 5 " 10 per million
- CMD (all types): 1 " 10 per 100,000
- FSH-MD: 1 per 20,000
- EDMD: 1 per 300,000
Risk Factors
Genetics
Genetic testing is clinically available for most MDs:
- Dystrophinopathies (DMD/BMD): X linked
- DMD exon duplication/deletion in 70% cases
- DMD point mutation in almost 30% cases
- New mutations of the dystrophin gene are common, and hence, most cases have no affected relatives despite X-linked recessive inheritance. New mutations in the dystrophin gene are found frequently in the mothers of affected boys.
- LGMD: Most childhood-onset LGMDs are autosomal recessive.
- Sarcoglycanopathies (LGMD2C " F) make up roughly 70% of childhood-onset LGMDs.
- LGMD2I (FKRP): 5% childhood-onset LGMDs
- CMD: most autosomal recessive (12 genes)
- Nonsyndromic (LAMA2, COL6A1 " COL6A3)
- Syndromic (e.g., POMT1, POMGT1, FKRP)
- FSH-MD: autosomal dominant (D4Z4 deletion)
- EDMD: X linked (EMD or FHL1 mutations) or autosomal dominant (LMNA mutation)
Pathophysiology
- Deficient or defective muscle fiber proteins causing fiber dysfunction and/or increased membrane fragility
- Muscle biopsy: Increased variability in muscle fiber size (i.e., degenerating, regenerating, and necrotic fibers), split muscle fibers and increased internal nuclei, fibrosis. Immunohistochemistry may note decreased/absent sarcolemmal proteins (e.g., DMD, LGMDs, CMDs).
Diagnosis
History
- Neonatal hypotonia, feeding difficulty (CMD)
- Gross motor delay/regression
- Global developmental delay (syndromic CMD) or learning disorders (DMD)
- Exercise intolerance/cramping
- Myalgia (BMD, DMD, FSH-MD)
- Seizures: merosin-negative and syndromic CMD
- DMD
- Onset typically <5 years old with gross motor delays, increasing falls, toe walking, and proximal muscle weakness (e.g., difficulty climbing stairs, rising from floor)
- Dependence on wheelchair for mobility usually between 8 and 12 years of age
- Calf pseudohypertrophy is common.
- Serum creatine kinase (CK) levels are markedly elevated (often >50 normal). Serum transaminases may be elevated (muscle origin).
- Higher incidence of learning difficulties, ADHD, autism, OCD. Loss of ambulation occurs around 13 " 16 years old. Incidence of cardiomyopathy increases with age, although respiratory muscle weakness (e.g., ineffective cough, hypoventilation, and eventual respiratory failure) is the cause of death in about 75% of DMD boys.
- BMD
- Milder version of DMD phenotype; onset typically >8 years old
- Boys remain ambulatory into their 20s.
- Higher incidence of myalgia, cramps, and myoglobinuria in BMD (vs. DMD)
- Rarely, cardiomyopathy may be sole or presenting feature.
- LGMD
- Proximal muscle weakness (neck flexors, hip flexors, shoulder girdle)
- Onset and progression highly variable
- Sarcoglycanopathies (LGMD2C " F) can mimic DMD (including calf pseudohypertrophy).
- Patients are cognitively normal.
- CMD
- Hypotonia, gross motor delay, weakness, and feeding difficulty typically noted from birth
- Two main groups of CMDs: (1) nonsyndromic CMD due to defective structural proteins (e.g., merosin-negative CMD, Ullrich/Bethlem MD) and (2) syndromic CMD due to defective glycosylation (e.g., Fukayama MD, muscle-eye-brain disease, Walker-Warburg syndrome)
- Most children with nonsyndromic CMD are cognitively normal. Seizures may occur in merosin-negative CMD (20 " 30%). Ullrich MD shows characteristic proximal contractures and distal joint hyperlaxity (fingers, toes). Bethlem MD shows proximal muscle weakness and distal contractures.
- Syndromic CMDs show variable severity, often associated with intellectual disability, eye manifestations, and brain anomalies (e.g., neuronal migration disorders, seizures, hydrocephalus).
- FSH-MD
- Onset typically <20 years old with facial weakness, scapular winging, and humeral (biceps, triceps) weakness
- Relative sparing of deltoid strength is seen.
- Rare infantile-onset cases have been reported.
- Retinal vasculopathy (Coates disease) and sensorineural hearing loss can occur.
- Cardiac arrhythmia is occasionally noted (<10%).
- EDMD
- Onset typically in 1st decade
- Patients initially present with joint contractures (neck, elbow, and ankles) disproportionate to degree of weakness.
- Muscle weakness and wasting develop in biceps, triceps, spinates muscles, and (later) tibialis anterior and peroneal muscles.
- Cardiac arrhythmias are common by 2nd decade.
- Pseudohypertrophy is not seen.
Physical Exam
- Facial weakness (FSH-MD)
- Pattern of muscle weakness and atrophy
- Scapular winging (FSH-MD)
- Pattern of joint contractures (EDMD) or joint hypermobility (Ullrich MD)
- Pattern of muscle pseudohypertrophy (e.g., calf muscles in DMD, BMD, LGMD)
- Reflexes normal to mildly decreased (except for joints with contractures). Reflexes are not lost until late in disease course.
- Normal sensory exam
- Scoliosis: rapid progression if nonambulatory
- Gower maneuver (when arising from sitting to standing position, patient must put his hand on his knees and "climb up himself " )
- Gait abnormalities (e.g., toe walking, exaggerated lumbar lordosis, Trendelenburg gait)
- Cardiomyopathy (tachycardia, hypotension)
- Respiratory weakness (weak cough)
Diagnostic Tests & Interpretation
Lab
- Serum CK
- Markedly elevated in DMD, BMD, some LGMD, and CMDs (e.g., Fukayama MD)
- CK may be normal late in disease owing to severe muscle atrophy.
- CK is typically normal in FSH-MD and some CMDs (e.g., Ullrich MD). Normal to mild CK elevation is seen in EDMD.
Diagnostic Procedures/Other
- Nerve conduction study: Merosin-negative CMD may show mild conduction velocity slowing.
- EMG: nonspecific myopathic changes
- MRI muscle: signal change noted reflecting muscle atrophy and fatty infiltration. May guide site of optimal muscle biopsy. Pattern of muscle involvement maybe helpful in diagnosis.
- MRI brain: Merosin-negative CMD shows diffuse white matter signal abnormalities (typically visible by 6 months old).
- Muscle biopsy can be used to confirm dystrophy (see "Differential Diagnosis "), whereas immunohistochemistry can help in diagnosis of nondystrophic MDs (e.g., LGMD) if DMD genetic testing is normal.
Differential Diagnosis
- Inflammatory myopathy (e.g., dermatomyositis)
- Metabolic myopathy
- Congenital myopathy
- Anterior horn cell disease (e.g., SMA)
- Polyneuropathy (e.g., CIDP)
- Myotonic dystrophy (different pathology)
Treatment
Medication
- Early attention should be directed to prevention of deformity that encumbers function with weakness and prevention of obesity.
- For DMD: Corticosteroids (prednisone [0.75 mg/kg/day] or deflazacort) 0.9 mg/kg/day: Improve muscle strength, prolong independent ambulation (mean = 2.5 years), delay onset of cardiomyopathy and scoliosis, and improve pulmonary function testing. Patients must be monitored for adverse effects of steroid therapy (weight gain, bone demineralization, behavior issues).
- All other MDs: no treatment
Additional Therapies
General Measures
- Supportive care (e.g., routine immunizations)
- Psychological and/or school support
- Night splinting (DMD, LGMD) to prevent progression of joint contractures
- Physiotherapy: passive stretching
- Orthopedic evaluation: scoliosis surveillance and/or management of joint contractures
- Genetic counseling
- Ophthalmology (retinal) evaluation (FSH-MD), cataract surveillance (DMD patients on steroids)
Additional Therapies
Several potential therapies for DMD are being studied (e.g., antisense oligonucleotide therapy, DMD nonsense mutation read-through therapy, myostatin inhibitor therapy, stem cell therapy). These therapies remain experimental and are not commercially available in North America or Europe.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Respiratory surveillance
- Baseline pulmonary evaluation (DMD, CMD) with periodic PFT surveillance, incentive spirometry, and/or cough assist devices
- Monitor for decline in PFT scores (especially FVC) and/or clinical evidence of nocturnal hypoventilation (e.g., morning headache/nausea, daytime somnolence, orthopnea). If noted, obtain sleep study to evaluate for potential need for nocturnal bilevel positive airway pressure (BiPAP).
- Monitor kyphoscoliosis.
- Orthopedic surveillance
- When progressive scoliosis is evident, treatment with spinal fusion is indicated to prevent deteriorating quality of life associated with severe deformity.
- Following loss of ambulation in DMD, affected boys are at high risk for progressive, collapse-type scoliosis and should be screened at 6 " 12-month intervals until young adult years.
- Cardiology surveillance
- Cardiomyopathy is well documented for many MDs, necessitating periodic echocardiogram and ECG surveillance studies for DMD, BMD, LGMD1B, LGMD2C " F (20 " 30% risk), LGMD2I (30 " 60% risk), merosin-negative CMD, and EDMD.
- American Academy of Pediatrics (AAP) guidelines recommend DMD patients receive complete cardiac evaluation every 2 years (until age 10 years) and annually thereafter.
- Cardiac arrhythmia surveillance is required for EDMD, LGMD1B, and FSH-MD (<10% risk); also consider for any MD patient showing echocardiogram evidence of a cardiomyopathy.
- Cardiac transplantation should be considered for BMD patients with severe cardiomyopathy, particularly if they have relatively minor skeletal muscle involvement.
Prognosis
- DMD: life expectancy into late 20s, death typically from respiratory failure. Life expectancy is improving with advances in care and realistic hope for specific therapies (fueled by these advances).
- BMD: life expectancy into mid-40s, death typically due to cardiomyopathy
- LGMD: variable. Sarcoglycanopathies may show a DMD-like progression. Autosomal dominant LGMD later onset with slow progression
- FSH-MD: Normal life expectancy
Additional Reading
- American Academy of Pediatrics. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics. 2005;116(6):1569 " 1573. [View Abstract]
- Bonnemann CG. Limb-girdle muscular dystrophy in childhood. Pediatr Ann. 2005;34(7):569 " 577. [View Abstract]
- B Άnnemann CG, Wang CH, Quijano-Roy S, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord. 2014;24(4):289 " 311.
- Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):77 " 93. [View Abstract]
- Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010;9(2):177 " 189. [View Abstract]
- El-Bohy A, Wong B. Muscular dystrophies. Pediatr Ann. 2005;34(7):525 " 530. [View Abstract]
- Guglieri M, Straub V, Bushby K, et al. Limb " girdle muscular dystrophies. Curr Opin Neurol. 2008;21(5):576 " 584. [View Abstract]
- Hermans MCE, Pinto YM, Merkies IS, et al. Hereditary muscular dystrophies and the heart. Neuromuscul Disord. 2010;20(8):479 " 492. [View Abstract]
- Kirschner J, Bonnemann C. The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries. Arch Neurol. 2004;61(2):189 " 197. [View Abstract]
- Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2006;34(1):1 " 15. [View Abstract]
Codes
ICD09
- 359.1 Hereditary progressive muscular dystrophy
- 359.0 Congenital hereditary muscular dystrophy
- 359.21 Myotonic muscular dystrophy
ICD10
- G71.0 Muscular dystrophy
- G71.2 Congenital myopathies
SNOMED
- 73297009 muscular dystrophy (disorder)
- 111501005 Congenital hereditary muscular dystrophy (disorder)
- 76670001 Duchenne muscular dystrophy (disorder)
- 387732009 Becker muscular dystrophy (disorder)
- 93153005 Limb-girdle muscular dystrophy (disorder)
FAQ
- Q: What test should be ordered first in a boy with suspected DMD?
- A: After confirmation that CK is elevated, 1st-line testing is DMD duplication/deletion analysis (detects 70% cases). If negative, DMD gene should be sequenced. Muscle biopsy is typically reserved for patients with negative genetic testing (i.e., LGMD) or if there is clinical suspicion for inflammatory myopathy (e.g., dermatomyositis). Nerve conduction studies can help differentiate neurogenic disorders (i.e., SMA, polyneuropathy) but show nonspecific myopathic changes in MDs.
- Q: What is the recurrence risk in DMD?
- A: About 2/3 of mothers of males with DMD are carriers. If a female DMD carrier has a son, that boy has a 50% chance of having DMD. If she has a daughter, that girl has a 50% chance of becoming a DMD carrier. Males with DMD or BMD will transmit the mutated gene to all daughters (who become carriers). The sons of DMD males will not be affected (X linked).
- Q: Can female DMD carriers be symptomatic?
- A: Yes. Owing to the random nature of X-chromosome inactivation, roughly 10% of female DMD heterozygotes may develop cardiomyopathy and/or proximal muscle weakness. The AAP recommends female carriers receive a cardiac evaluation in early adulthood and every 5 years after 25 " 30 years old.